Reduced levels of neurotransmitters including acetylcholine have been reported in dementias of the Alzheimer type. In particular, a deficit in acetylcholine-mediated transmission is thought to contribute to the cognitive and the neurobehavioral abnormalities associated with these disorders. Accordingly, drugs known to augment cholinergic transmission in the CNS are the mainstay of current therapy.
AChEIs are now not only part of the standard of care for patients suffering from a dementia of the Alzheimer type, but are also widely used off-label for various other chronic progressive disorders of cognitive function. AChEIs have the enhancement of acetylcholine-mediated neurotransmission as a general mechanism of action. All act in the human CNS to increase and prolong the availability of acetylcholine by inhibiting its degradatory enzyme acetylcholinesterase (AChE). Four AChEIs have been approved by the U.S. FDA for the treatment of Alzheimer's disease and for Parkinson's disease dementia: tacrine, donepezil [Aricept®], rivastigmine [Exelon®] and galantamine [Razadyne®]. AChEIs are available in various formulations including immediate release forms such as tablets, capsules and solutions as well as rapid dissolving and extended release forms for oral administration as well as those for parenteral (e.g. transdermal) administration.
In particular, tacrine is presented in capsules containing 10, 20, 30, 40 mg/capsule and is used at recommended daily dosages of from 40 to 160 mg (divided into 4 doses); donepezil is presented, as hydrochloride, in orally disintegrating tablets or in tablets to be swallowed containing 5 or 10 mg/tablet to be administered once a day and is used at recommended daily dosages of from 5 to 10 mg, and as a dose formulation containing 23 mg of donepezil HCl in a matrix type tablet to be administered once a day; rivastigmine is presented in capsules containing the hydrogen tartrate in amounts corresponding to 1.5, 3, 4.5 and 6 mg of rivastigmine base, as oral solution containing the tartrate corresponding to 2 mg of rivastigmine base and in form of a transdermal patch releasing rivastigmine at 4.6 mg/24 hours or 9.5 mg/24 hours, the recommended daily dosage for the IR forms being of from 6 to 12 mg, divided into 2 doses and the maximal studied patch dose being 13.3 mg/24 hours the maximal recommended patch dose being 18 mg/24 hours; and galantamine is available in ER capsules of 8 mg, 16 mg and 24 mg containing 10.253 mg, 20.506 mg and 30.758 mg, respectively, of galantamine hydrobromide, or in IR tablets containing 5.126, 10.253, and 15.379 mg of galantamine hydrobromide, respectively, corresponding to 4 mg, 8 mg and 12 mg, respectively, of galantamine base and as a 4 mg/mL oral solution, the recommended daily dosage being from 16 mg to 32 mg, in the United States of America the maximum recommended daily dose having been reduced to 24 mg divided into 2 doses.
Brief reviews of the efficacy of the AChEIs rivastigmine, donepezil and galantamine for the treatment of dementia diseases, by Angelescu et al., have been published in MMW-Fortschr. Med. Sonderheit, 2007, 149, 76-78 (“Angelescu 2007”) and in the Cochrane Database Syst Review, 2006, Jan. 25(1): CD005593 (“Birks, 2006”).
Other AChEIs, in particular tacrine analogs, such as ipidacrine; phenserine and their analogs; icopezil; and zanapezil are under evaluation. For example, phenserine is administered in IR 15 mg tablets and has been studied at a daily dose of 30 mg.
AChEIs vary in their pharmacological profiles and in their affinities for acetylcholinesterase and butyrylcholinesterase. Donepezil and galantamine are 1000- and 50-fold, respectively, more selective for acetylcholinesterase than for butyrylcholinesterase, whereas rivastigmine inhibits both enzymes with similar affinity (Thomsen et al., Life Scie. 1990, 46, 1553-58) and certain analogs of phenserine are more selective for butyrylcholinesterase (see for example Qian-sheng Yu et al., J Med Chem, 1997, 40(18), 2895-2898 and U.S. Pat. No. 6,683,105).
Carefully conducted clinical trials of donepezil (Rogers et al., Neurology 1998, 50, 136-45; Winblad et al. Neurology. 2001 Aug. 14; 57(3):489-95), rivastigimine (Rösler et al., Brit. Med. J. 1999, 318, 633-38; Farlow et al. Eur. Neurol., 2000, 44, 236-41) and galantamine (Raskind et al., Neurology, 2000, 54, 2261-68; Tariot et al., Neurology, 2000, 54, 2269-76) in patients with dementias of the Alzheimer type demonstrated small, but statistically significant, benefits on cognitive and global measures relevant to dementia. The magnitude of the effect in pivotal clinical trials was on the order of a 2.8 point improvement on the 70-point cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), or 1-1.5 point improvement on the 30-point Mini-Mental Status Examination (MMSE) compared to placebo over six months. Differences in global measures assessed by the 7-point Clinician Interview-Based Impression of Change scale (CIBIC) were on the order of 0.3-0.5 points in patients receiving an AChEI compared to those receiving placebo. Efficacy was similar for the three commonly used AChEIs. AChEIs also appear to have a beneficial effect on the behavioral and neuropsychiatric symptoms in patients with Alzheimer type dementias. Moreover, rivastigmine was given open-label to patients with Parkinson's disease (PD) at an initial dose of 1.5 mg twice a day and the dose was increased after 4 weeks to 3 mg twice daily, after 8 weeks to 4.5 mg twice daily and after 12 weeks to a maximal dose of 6 mg twice daily by trying to keep the dose of rivastigmine constant at the maximal tolerated dose, between weeks 12 and 26 of the trial. According to the Authors, rivastigmine may improve the cognitive functions in PD patients with dementia with no worsening of motor function. (Giladi et al., Acta Neurol Scand 2003, 108, 368-373).
Unfortunately, however, none of the currently available medications offer more than modest clinical benefit for some patients suffering from any of the aforementioned dementing disorders, even when these medications are administered at their maximum safe and tolerated doses. This is the first problem limiting the success of current AChEI therapy of Alzheimer type dementias.
A second problem limiting the success of current AChEI therapy of Alzheimer type dementias is that, even at recommended amounts, all these drugs produce dose limiting adverse reactions, mainly by over-stimulating peripheral cholinergic receptors of the muscarinic type. As a result, signs and symptoms of untoward gastrointestinal, pulmonary, cardiovascular, urinary, and other systems dysfunction occur. These side effects commonly include, for the aforementioned AChEIs tacrine, donepezil, rivastigmine and galantamine: anorexia, nausea, vomiting, diarrhea, abdominal pain, weight loss; increased bronchial secretions, dyspnea, bronchoconstriction and bronchospasm; bradycardia, supraventricular cardiac conduction abnormalities, vasodilation, hypotension, dizziness and syncope; urinary bladder spasm, increased urinary frequency, and incontinence; flushing and diaphoresis; fatigue, headache, lacrymation, miosis, and loss of binocular vision (Physicians' Desk Reference 2008, Thomson P D R, Montvale, N.J.).
Adverse events attending the use of AChEIs appear to primarily reflect the excessive stimulation of peripheral cholinergic receptors, especially those of the muscarinic type (mAChRs). Five subtypes of muscarinic receptors, M1 through M5, have now been identified. Ongoing research has begun to map the distribution and physiologic role of these receptors as well as determine the binding affinity of drugs to them. For example, M1 receptors are found in sympathetic postganglionic neurons (autonomic ganglia), in gastric tissue and in the myenteric plexus; they are involved in secretions from salivary glands and the gastrointestinal tract. M2 receptors are present in cardiac and smooth muscle and have been implicated in the regulation of contractile forces of the atrial cardiac muscle and the conduction velocity of the atrioventricular node and thus heart rate. M2 receptors are also present on gastrointestinal smooth muscle as well as on detrusor smooth muscle cells and other structures within the bladder wall. M3 receptors are the predominant muscarinic receptor subtype mediating contraction of the stomach fundus, urinary bladder, and trachea. They are also expressed on glandular cells including gastric parietal cells and on vascular smooth muscle as well as detrusor smooth muscle and other structures within the bladder wall. M3 receptors are involved in exocrine gland secretion, smooth muscle contractility, emesis, pupil dilatation, food intake and weight gain.
It is also known that the degree to which AChEIs can attenuate the activity of this enzyme (acetylcholinesterase, AChE) in the CNS can be estimated by assays of AChE activity and related protein levels in the CSF and by use of cerebral imaging technology. It is reported that recommended maximal dose levels of these drugs typically achieve only about 35% AChE inhibition (without a concomitant increase in AChE protein levels) in the CNS of Alzheimer disease patients (Brannan S et al. ACNP 46th Annual Meeting, Program No. 4. Boca Raton Fla., Dec. 10, 2007—“Brannan 2007”; Farlow M et al AAN Poster 2008; Davidsson P et al Neurosci Lett 2001; 300:157-60; Amici S et al Mech Ageing Dev 2001; 122:2057-62) and that inhibition of AChE activity and cognitive improvement are significantly correlated (Giacobini et al. J Neural Transm. 2002 July; 109(7-8):1053-65; Darreh-Shori T et al, J Neural Trans 2006; 113:1791-801) and that, ordinarily, a higher degree of enzyme blockade must be attained for maximum functional effect (Jann et al., Clin Pharmacokinet. 2002; 41(10):719-39—“Jann 2002”).
On the other hand, doubling the dose of rivastigmine, which became clinically practical when AChEI administration by immediate release tablets was replaced by skin patches, which diminished side effects by blunting peak blood levels, significantly increased the amount of cognitive improvement in patients with Alzheimer's disease without increasing side effects. Similarly, a 23 mg dose of donepezil formulated in a matrix type tablet that tends to smooth out the sharp rise in peak drug concentrations following once daily administration and facilitates the tolerable administration of a 23 mg dose, produces a significantly greater cognitive benefit in Alzheimer Disease (AD) patients than the earlier 10 mg immediate-release dose formulation (Farlow et al, 2010).
The precise causes of the vomiting and related gastrointestinal symptoms so frequently induced by AChEI therapy are not established. Presumably, they reflect cholinergic receptor hyperstimulation attending AChEI administration. Vomiting is coordinated in a center located at the base of the brain. The vomiting center communicates with the nearby chemoreceptor trigger zone, whose stimulation can lead to such complaints of gastrointestinal distress as anorexia, nausea and vomiting.
By virtue of being dose limiting, adverse effects also constrain the efficacy of AChEI therapy. Studies in animal models of human cognitive dysfunction indicate a direct dose-response relation between the amount of acetyl choline esterase inhibition and the degree of cognitive improvement (Bennett B M et al., Neuropsychopharmacology. 2007 March; 32(3):505-513). Similar conclusions have been drawn regarding AChEI effects on cognitive and behavioral symptoms in human patients with Alzheimer's disease (Jann 2002; Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, Zechner S, Nagel J, Lane R. Int J Geriatr Psychiatry. 2007 May; 22(5):456-67).
As set forth above, use of an AChEI to treat dementias of the Alzheimer type combined with a nsPAChA, which alleviates the peripheral cholinergic side effects of the AChEI, or combined with a naAEA, which alleviates nausea and vomiting caused by the AChEI, fails to realize the full potential benefits of this approach to therapy. While potentially lessening side effects and thereby enabling the use of higher and thus more effective doses of the AChEI, merely employing the concomitant use of antiemetics, such as domperidone and others, or of anticholinergics such as propantheline, oxybutynin, tolterodine and others, falls short of achieving the utmost therapeutic advantages of AChEIs in the treatment Alzheimer type dementias. Further implementation of this concept will confer far greater advantage to individuals suffering from these disorders.
An improvement in the treatment of Alzheimer type dementia is attained by a combined therapy associating an nsPAChA, at a dose of from 20% to 200% the current daily doses, with an AChEI, at a dose up to 4 times the maximal tolerated dose of said AChEI when administered alone, as disclosed in WO 2009/120277. By such a treatment, a higher acetylcholinesterase inhibition in the CNS is achieved and greater relief of the symptoms of Alzheimer type dementia is enabled, by concomitantly decreasing concurrent adverse effects.
Similarly, WO 2011/034568 discloses an improvement in the treatment of Alzheimer type dementia which is attained by a combined therapy associating a non-anticholinergic-antiemetic agent, at a dose of from 50% to 300% the current IR daily doses, with an AChEI, at a dose up to 3 times the recommended doses of said AChEI when administered alone.
Notwithstanding the real progress achieved by treating Alzheimer disease patients with up to 200% of the nsPAChA currently used doses in IR or ER forms or with up to 300% of the naAEAs currently used doses in IR forms together with AChEIs, there is a need for further increasing AChE inhibition in the CNS of said patients.
There is substantial evidence from preclinical studies that AChEIs may affect basic processes that have been implicated in Alzheimer Disease (AD) pathogenesis, suggesting that these drugs could have both disease-modifying and neuroprotective effects in humans. The evidence seems to be strongest in relation to donepezil (reviewed in Jacobson and Sabbagh, 2008). There is also evidence from studies in Alzheimer patients that these treatments could slow disease progression. For example Roundtree et al, (2009) report on 20-year retrospective study conducted at an Academic center in 641 Alzheimer patients. In a linear model, greater anti-dementia drug use was significantly associated with slower rate of decline as measure on the Mini Mental State Examination (MMSE; p<0.0001), the ADAS-Cog (p<0.01), the Physical Self-Maintenance Scale (PMS; p<0.05), the Instrumental Activities of Daily Living (IADL; p<0.0001) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB; p<0.001). The magnitude of the treatment effect, however, was small. Rate of change in mean scores indicated that treated patients would have declined less on the rating scales: 1 point/year on the MMSE, 0.4 points/year on the PMS, 1.4 point/year on the IADL, and 0.6 point/year on the CDR-SB. Although clinically and statistically significant, these treatment effects remain modest (Shanks et al, Cholinesterase inhibition: is there evidence for disease-modifying effects? Curr Med Res Opin, 2009, 25: 2439-46).
Studies in animal models of AD show a dose-response for neuro-protection and suggest that the doses currently used in patients may be too low for disease modification (i.e, slowing of disease progression). For example, a study by Dong et al (Hongxin Dong, Carla M. Yuede, Carolyn A. Coughlan, Keely M. Murphy, and John G. Csernansky. Effects of Donepezil on Amyloid-β and Synapse Density in the Tg2576 Mouse Model of Alzheimer's Disease Brain Res. 2009 Dec. 15; 1303: 169-178) examined a possible neuro-protective effect of donepezil in a transgenic mouse model of AD, the Tg2576 mouse model of AD. This model overexpresses the human amyloid precursor protein (hAPP), and is one of the most well characterized mouse models of AD. In this model, at approximately 9 months of age, A-beta deposits appear in cortical and limbic brain regions and indications of cellular inflammation and behavioral deficits emerge (reviewed in Dong et al, 2009). In a previous study, Dong et al, (Hongxin Dong, Cynthia A. Csernansky, Maureen V. Martin, Amy Bertchume, Dana Vallera, and John G. Csernansky. Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer's disease. Psychopharmacology (Berl). 2005 August; 181(1): 145-152) had shown that donepezil (0.1, 0.3 and 1.0 mg/kg for 6 weeks) improved learning and memory functions in Tg2576 mice, but did not affect A-beta deposition. In the “neuroprotective study,” (Dong et al, 2009), higher doses of donepezil (0, 1, 2, and 4 mg/kg/day) were administered chronically in drinking water to Tg2576 mice beginning at 3 months and ending at 9 months of age, when A-beta deposits and behavioral deficits usually become apparent. Concentrations of A-beta, synaptic protein (synaptophysin) and synapse density in the hippocampus were measured following the long-term administration of donepezil. Results showed that administration of 4 mg/kg/day of donepezil, as compared to vehicle, significantly reduced brain tissue soluble A-beta1-40 and 1-42, A-beta plaque number and burden. Furthermore, donepezil 4 mg/kg also significantly increased synaptic density in the molecular layer of the dentate gyms of Tg2576 mice. Lower doses of donepezil (1 and 2 mg/kg) were not effective on these parameters. Taken together the results of the study show that a dose of 4 mg/kg/day of donepezil is neuroprotective in a mouse model of AD, but lower doses were not effective. Thus, in Alzheimer patients, the administration of doses higher than the currently approved doses of donepezil should be neuroprotective and should slow disease progression. A similar dose-related neuroprotective effect has also been observed with rivastigmine and other AChEIs (Shanks et al. Cholinesterase inhibition: is there evidence for disease-modifying effects? Curr Med Res Opin 2009, October; 25 (10): 2439-46).
Thus, by further increasing the safe and tolerable dose of an AChEI it will be possible to take advantage of their enhanced pharmacological activity not only in relation to palliative effects but also in relation to neuroprotective effects, thus retarding progression of the underlying dementing disorder.
However, as set forth above, even by using the method disclosed in WO 2009/120277 or WO 2011/034568, it is presently not possible to increase also beyond 4-times the therapeutic dose of AChEI to be administered to a patient without inducing intolerable cholinergic or emetic, from any origin, adverse effects, as those described above.
In particular, the increase of the AChEI doses by the concurrent suppression of the peripheral cholinergic adverse effects, including emesis, does not completely suppress vomiting caused by AChEI overdoses and, in any case, an antiemetic agent must be added to the AChEI. By consequence, if the AChEI doses are increased, the treated subject should take either a triple nsPAChA/AChEI/naAEA combination or an nsPAChA/AChEI fixed combination and an antiemetic. Under these conditions, on one side, it could be difficult to adjust the AChEI doses in function of both the co-administered nsPAChA and antiemetic agent, and, on the other side, the administration of a triple combination providing concurrent or sequential, but separate AChEI, nsPAChA and antiemetic administrations could give rise to dangerous and even fatal mistakes in said administrations, especially in the context of the population suffering from a dementia of Alzheimer type.
The present invention is directed to overcoming these and other deficiencies in the art.